bims-unfpre Biomed News
on Unfolded protein response
Issue of 2026–07–26
six papers selected by
Susan Logue, University of Manitoba
  1. Dual regulation of the unfolded protein response by IGF2BP3 during ER stress.
  2. The PERK paradox in aging: how ER stress shapes senescence and neurodegeneration.
  3. Structural dynamics of IRE1 and its interaction with unfolded peptides.
  4. Vitamin D3 reverses intestinal epithelial cell injury in septic rats by alleviating toll-like receptor 4 mediated endoplasmic reticulum stress.
  5. Oxidative protein folding and Ca2+ homeostasis under redox control.
  6. ER-mitochondria contact sites and organelle stress in asthma.
  1. Genes Dev. 2026 Jul 23.
    Dual regulation of the unfolded protein response by IGF2BP3 during ER stress.
    Aleksandra S Anisimova, Sabina Omerbegovic, Milica Mihailovic, Sascha Gratzl, Harald Hornegger, Irmgard Fischer, Gijs A Versteeg, Stefan L Ameres, G Elif Karagöz.
      Misfolded protein accumulation in the endoplasmic reticulum (ER) perturbs cellular homeostasis, causing pathological ER stress. While a transcriptional response is paramount for the unfolded protein response (UPR), which counters ER protein stress, multiple UPR-linked mRNAs are posttranscriptionally regulated. However, the mechanisms mediating this regulation remain unclear. Here, we reveal specific interactions between the conserved RNA-binding protein IGF2BP3 and transcripts encoding UPR effectors. During ER stress, IGF2BP3 destabilizes many of its target transcripts, including UPR effectors. Mechanistically, ER stress enhances IGF2BP3's association with the mRNA decapping complex and the ER stress sensor RNase IRE1, which correlates with a shift toward mRNA destabilization. Unexpectedly, prolonged depletion of IGF2BP3 inhibits the UPR via decreased transcription of UPR target genes. Together, our findings suggest that IGF2BP3 contributes to proteostasis during ER stress through a dual mechanism: directly promoting mRNA degradation to reduce translation and folding burden and indirectly supporting transcriptional activation of the UPR.
    Keywords:  IGF2BP3; IRE1; RNA-binding proteins; endoplasmic reticulum; mRNA decapping complex; posttranscriptional regulation; unfolded protein response
    DOI:  https://doi.org/10.1101/gad.353291.125
  2. Geroscience. 2026 Jul 22.
    The PERK paradox in aging: how ER stress shapes senescence and neurodegeneration.
    Vivek Pandey, Rahul Sachdeva, Sanda Despa.
      Endoplasmic reticulum (ER) stress and activation of the unfolded protein response (UPR) are now recognized as integral components of the proteostasis network that preserves cellular and tissue function across the lifespan. With aging, increasing oxidative load, metabolic imbalance, and Ca2⁺ dysregulation elevate the burden of misfolded proteins in the ER, leading to progressive UPR engagement. When ER stress is mild or transient, UPR signaling restores folding capacity, restrains translation, and enhances redox and degradative programs, thereby promoting cellular resilience. In contrast, persistent or repeatedly unresolved ER stress narrows this adaptive window and biases UPR outputs toward chronic inflammation, stable growth arrest, and cell loss processes that collectively drive inflammaging, stem/progenitor exhaustion, tissue degeneration, and vulnerability to neurodegenerative disease. This review synthesizes evidence that ER stress is not merely a correlation of aging but a mechanistic contributor to age-related decline, with senescence emerging as a major downstream fate in multiple tissues. It also highlights how context- and duration-dependent PERK signaling can be protective early, yet maladaptive when chronically engaged, shaping senescence programs and influencing neuronal survival and neurodegenerative disease progressions. Finally, this review discusses therapeutic opportunities and open questions centered on restoring adaptive PERK/ISR dynamics to support healthy aging.
    Keywords:  Aging; ER stress; Neurodegeneration; Senescence; Unfolded protein response
    DOI:  https://doi.org/10.1007/s11357-026-02430-5
  3. Elife. 2026 Jul 23. pii: RP106716. [Epub ahead of print]14
    Structural dynamics of IRE1 and its interaction with unfolded peptides.
    Elena Spinetti, Grzegorz Ścibisz, Gülsün Elif Karagöz, Roberto Covino.
      The unfolded protein response (UPR) is a crucial signaling network that preserves endoplasmic reticulum (ER) homeostasis, impacting both health and disease. When ER stress occurs, often due to an accumulation of unfolded proteins in the ER lumen, the UPR initiates a broad cellular program to counteract cytotoxic effects. Inositol-requiring enzyme 1 (IRE1), a conserved ER-bound protein, is a key sensor of ER stress and activator of the UPR. While biochemical studies confirm IRE1's role in recognizing unfolded polypeptides, high-resolution structures showing direct interactions remain elusive. Consequently, the precise structural mechanism by which IRE1 senses unfolded proteins is debated. In this study, we employed advanced molecular modeling and 137 µs of atomistic molecular dynamics simulations to clarify how IRE1 detects unfolded proteins. Our results demonstrate that IRE1's luminal domain directly interacts with unfolded peptides and reveal how these interactions can stabilize higher-order oligomers. We provide a detailed molecular characterization of unfolded peptide binding, identifying two distinct binding pockets at the dimer's center, separate from its central groove. Furthermore, we present high-resolution structures illustrating how BiP associates with IRE1's oligomerization interface, thus preventing the formation of larger complexes. Our structural model reconciles seemingly contradictory experimental findings, offering a unified perspective on the diverse sensing models proposed. We elucidate the structural dynamics of unfolded protein sensing by IRE1, providing key insights into the initial activation of the UPR.
    Keywords:  IRE1; S. cerevisiae; UPR; endoplasmic reticulum; human; molecular biophysics; structural biology
    DOI:  https://doi.org/10.7554/eLife.106716
  4. Sci Rep. 2026 Jul 21.
    Vitamin D3 reverses intestinal epithelial cell injury in septic rats by alleviating toll-like receptor 4 mediated endoplasmic reticulum stress.
    Ting Li, Dapeng Zhang, Xue Wu, Lihong Dong, Yijie Wang.
      Vitamin D3 has been shown to exert a protective effect on intestinal barrier function in sepsis. TLR4 may be a key link in this process. However, the precise mechanism of action in intestinal epithelial cells during sepsis remains unclear. A rat sepsis model was established by CLP.VD3 was administered via intraperitoneal injection at 50 µg/kg. IHC was employed to detect TLR4 and Lgr5 + cells. AB-PAS staining identified goblet cells. HE staining evaluated Paneth cells. LYZ and DEF-5 expression was performed to assess the function of Paneth cells. RT-PCR detected MUC1, MUC2 and VDR expression. Western blotting detected intestinal tight junction proteins and ER stress biomarkers.16S rRNA gene sequencing characterized gut microbiota composition, and functional potential was predicted using KEGG pathway analysis. Following VD3 intervention, TLR4 expression in the intestinal tissue of septic rats was significantly reduced. Histological improvements included less intestinal epithelial degeneration and shedding, repaired mucosa, villus hyperplasia, and a more ordered villous arrangement. Paneth cell and goblet cell numbers significantly increased, along with their restoration of secretory function. Tight junction protein expression was improved, and overactivated IRE1/sXBP1-mediated ER stress was markedly inhibited. Interestingly, Lgr5 + intestinal stem cell numbers were paradoxically elevated in the sepsis group and were reduced following VD3 intervention, suggesting a shift from excessive proliferation toward differentiation that facilitates mucosal repair. VD3 treatment also improved gut microbiota diversity, partially restored the Firmicutes/Proteobacteria ratio, and specifically enriched Dubosiella as identified by LEfSe analysis. Our results suggest that VD3 ameliorates sepsis-induced intestinal epithelial cell injury by suppressing TLR4-mediated IRE1/sXBP1 ER stress, restoring Paneth and goblet cell number and secretory function, improving intestinal mechanical barrier integrity, and reshaping gut microbiota toward a more eubiotic configuration. The reduction in Lgr5 + ISC numbers following VD3 intervention likely reflects a shift from excessive self-proliferation toward differentiation, facilitated by normalization of the inflammatory stem cell niche, restoration of balanced Wnt/Notch signals from recovered Paneth and goblet cells, and VD3-induced microbiota changes that promote epithelial maturation.
    Keywords:  ER stress; Gut microbiota; Intestinal epithelial cells; Sepsis; TLR4
    DOI:  https://doi.org/10.1038/s41598-026-62715-9
  5. Cell Mol Life Sci. 2026 Jul 22.
    Oxidative protein folding and Ca2+ homeostasis under redox control.
    Jiro Ogura, Junichi Fujii, Hiroaki Yamaguchi.
      Secretory and membrane proteins undergo oxidative folding, the process of forming disulfide bonds between cysteine side chains to construct a stable higher-order structure, primarily in the endoplasmic reticulum (ER) followed by further post-translational modification in the Golgi apparatus, after which proteins proceed to pathways for secretion and membrane localization. Proteins involved in transferring oxidizing power to target proteins possess a pair of highly reactive forms of cysteine residue that mediate reduction-oxidation (redox) reactions. Oxidizing power, which is generally provided in the form of reactive oxygen/reactive nitrogen oxide species. Endoplasmic reticulum oxidoreductin 1 (ERO1) is the ancient ER oxidase that utilizes molecular oxygen to produce hydrogen peroxide, which is then utilized for thiol oxidation to form a disulfide bridge in target proteins. Excessive elevation of these species could promote aberrant oxidation of susceptible molecules, which could lead to an accumulation of misfolded proteins and consequent ER stress. The ER is also involved in cellular Ca2+ signaling in which Ca2+-pump ATPase and Ca2+ release channels coordinate to play essential roles. Ca2+ regulates the activity of some redox-reactive proteins, which are largely in the family of protein disulfide isomerase. Thus, the Ca2+ status indirectly associates with the oxidative folding of nascent proteins. Upon extensive oxidation, inactivation of the Ca2+-pump ATPase and inappropriate Ca2+ leak via the Ca2+ channels causes a depletion of Ca2+ in the ER lumen. When intracellular calcium is depleted, stromal interaction molecules (STIM) in the ER membrane sense the Ca2+ status within the ER lumen. STIM differentially regulates two types of Ca2+ channels in the plasma membrane: Ca2+-release-activated Ca2+ channel (ORAI), and voltage-operated Ca2+ channel (CaV1.2). This regulation coordinately maintains Ca2+ homeostasis within cells. Moreover, Zn2+ and H+ indirectly affect the potential of redox responses through controlling ER chaperone molecules. The redox capacity of the ER is maintained by resident proteins and small compounds, which include cations Ca2+, Zn2+ and H+, and hence the comprehensive care of them is necessary in order to maintain normal ER function.
    Keywords:  Calcium transport; Electron transfer; Glycosylation; Peroxiredoxin 4; Unfolded protein response (UPR)
    DOI:  https://doi.org/10.1007/s00018-026-06263-5
  6. Mol Biol Rep. 2026 Jul 22. pii: 1236. [Epub ahead of print]53(1):
    ER-mitochondria contact sites and organelle stress in asthma.
    Sihao Zhu, Xinxin Xing, Jia Zheng, Hai Wang.
      Mitochondria-associated endoplasmic reticulum membranes (MAMs), functional domains within endoplasmic reticulum (ER)-mitochondria contact sites, provide spatial domains through which ER-derived Ca²⁺ signals are coupled to mitochondrial metabolism, redox balance, and stress adaptation. In asthma, this concept is relevant because many disease-associated stimuli, including allergens, cytokines, oxidative stress, infection-related signals, and mechanical stress, disturb both ER and mitochondrial homeostasis. However, MAMs should not be used as a general label for all ER stress or mitochondrial dysfunction. Their unique value lies in explaining how selected stress signals are organized at sites of ER-mitochondria communication. This review critically evaluates whether MAM-related mechanisms contribute to asthma pathogenesis and where the current evidence remains indirect. The strongest asthma-relevant support is found in monocyte/macrophage-centered inflammatory responses, in which ER-mitochondria Ca²⁺ transfer, mitochondrial stress, and inflammasome activation may be functionally connected. In airway epithelial cells and airway smooth muscle cells (ASMCs), available studies more consistently support mitochondrial dysfunction, Ca²⁺ dysregulation, oxidative stress, barrier injury, cell death, and remodeling-related responses, but direct evidence that these changes are initiated by defined MAM remodeling remains limited. We therefore distinguish MAM-specific mechanisms from MAM-adjacent ER or mitochondrial stress responses across different asthma-relevant cell types. By organizing the literature around ER-to-mitochondria Ca²⁺ transfer, contact-site remodeling, mitochondrial stress signaling, and cell type-specific inflammatory or remodeling outcomes, this review highlights both the potential importance and the current limitations of MAM biology in asthma. Future studies should combine structural assessment of ER-mitochondria contacts with functional readouts of Ca²⁺ transfer, mitochondrial redox state, mitophagy, inflammasome activation, and disease-relevant cellular phenotypes. Such work will be essential to determine whether MAMs are causal regulators of asthma pathology or stress-responsive interfaces associated with broader organelle dysfunction.
    Keywords:  Asthma; ER–mitochondria contact sites; Mitochondria-associated endoplasmic reticulum membranes; NLRP3 inflammasome; Organelle stress
    DOI:  https://doi.org/10.1007/s11033-026-12441-2
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